Fic-mediated AMPylation tempers the unfolded protein response during physiological stress.

The proper balance of synthesis, folding, modification, and degradation of proteins, also known as protein homeostasis, is vital to cellular health and function. The unfolded protein response (UPR) is activated when the mechanisms maintaining protein homeostasis in the endoplasmic reticulum become overwhelmed. However, prolonged or strong UPR responses can result in elevated inflammation and cellular damage. Previously, we discovered that the enzyme filamentation induced by cyclic-AMP (Fic) can modulate the UPR response via posttranslational modification of binding immunoglobulin protein (BiP) by AMPylation during homeostasis and deAMPylation during stress. Loss of fic in Drosophila leads to vision defects and altered UPR activation in the fly eye. To investigate the importance of Fic-mediated AMPylation in a mammalian system, we generated a conditional null allele of Fic in mice and characterized the effect of Fic loss on the exocrine pancreas. Compared to controls, Fic-/- mice exhibit elevated serum markers for pancreatic dysfunction and display enhanced UPR signaling in the exocrine pancreas in response to physiological and pharmacological stress. In addition, both fic-/- flies and Fic-/- mice show reduced capacity to recover from damage by stress that triggers the UPR. These findings show that Fic-mediated AMPylation acts as a molecular rheostat that is required to temper the UPR response in the mammalian pancreas during physiological stress. Based on these findings, we propose that repeated physiological stress in differentiated tissues requires this rheostat for tissue resilience and continued function over the lifetime of an animal.

Evaluación de la técnica de conteo de grasas y ajuste de enzimas pancreáticas en un grupo de pacientes con insuficiencia pancreática secundaria a fibrosis quística con seguimiento en un hospital de alta complejidad / Evaluation of the fat counting technique and pancreatic enzyme adjustment in a group of patients with pancreatic insufficiency secondary to cystic fibrosis followed-up in a tertiary-level hospital

Objetivo: evaluar la efectividad de la técnica de conteo de grasas y ajuste de enzimas pancreáticas en un grupo de pacientes con insuficiencia pancreática secundaria a fibrosis quística (FQ). Materiales y métodos: En un grupo de pacientes con FQ, sin otra patología asociada, mayores de 1 año, con >10 000 UKD (unidades por kilo por día) de lipasa; se realizó educación y aplicación de técnica de conteo de grasas con ajuste enzimático, solicitando Van de Kamer y registro alimentario de 5 días durante la recolección de la muestra con un intervalo de 3 meses entre ambas determinaciones. Se evaluó la efectividad de la misma y las dosis de enzimas utilizadas mediante el porcentaje de excreción grasa (PEG), así como las variaciones en la cantidad de enzimas utilizadas y la ganancia de peso. Los datos se registraron en RED Cap (Research Electronic Data Capture) y se analizaron mediante Stata 12. Resultados: De un total de 21 pacientes, 16 completaron la intervención. El 50% presentó un índice de masa corporal (IMC) mayor del Plo 25 antes y después, un 87% alcanzó adecuación calórica mayor del 120% de la ingestas diarias recomendadas (RDA) al final, logrando un aumento promedio de z score de peso de 0,28 con una media inicial de 17 kg y final de 18,2 kg. En cuanto a la media del requerimiento enzimático fue de 14 800 UKD antes y 10 145 UKD después (z=0,002), asimismo el porcentaje de excreción grasa (PEG) tuvo una disminución del 38% (p=0,1705). Conclusiones: La implementación de la técnica de conteo de grasas y ajuste enzimático, podría ser una estrategia válida para aquellos pacientes con FQ que tienen dosis altas de enzimas e inadecuada ganancia de peso (AU)

Objective: To evaluate the effectiveness of the fat counting technique and pancreatic enzyme adjustment in a group of patients with pancreatic insufficiency secondary to cystic fibrosis (CF). Materials and methods: A group of patients with CF without other associated diseases, older than 1 year of age, lipase dose >10 000 UKD (units per kilo per day), received education on the fat counting technique with enzyme adjustment followed by its implementation of the intervention. Van de Kamer was requested and a 5-day food record was kept during the sample collection with an interval of 3 months between both measurements. The effectiveness of the technique and the enzyme doses used were evaluated based on the percentage of fat excretion (PFE), as well as the variations in the amount of enzymes used and weight gain. Data were recorded in RED Cap (Research Electronic Data Capture) and analyzed using Stata 12. Results: Of a total of 21 patients, 16 completed the intervention. Fifty percent had a body mass index (BMI) greater than Plo 25 before and after the intervention; 87% had achieved a caloric increase greater than 120% of the recommended daily intake (RDA) at the end of the study and an average increase in weight z score of 0.28 with an initial mean of 17 kg and a final mean of 18.2 kg. Mean enzyme requirement was 14 800 UKD before and 10 145 UKD after the intervention (z=0.002). PFE decreased by 38% (p=0.1705). Conclusions: The implementation of the technique of fat counting and enzyme adjustment may be a valid strategy for CF patients with high enzyme doses and inadequate weight gain. (AU)

Pancreatic Enzyme Replacement Therapy for Patients Diagnosed With Pancreaticobiliary Cancer: Validation of an Algorithm for Dose Escalation and Management.

OBJECTIVE: An algorithm was designed aiming to provide consistency of pancreatic enzyme replacement therapy (PERT) dosing/titration across healthcare professionals in pancreaticobiliary cancers (PBCs). This prospective observational study aimed to validate this algorithm. METHODS: Consecutive patients with inoperable or postoperative PBC with pancreatic exocrine insufficiency (PEI) symptoms, not taking PERT, or taking below the algorithm "starting dose," were eligible. A dietitian or clinical nurse specialist reviewed patients for up to 3 weeks, titrating PERT as per the algorithm. Feasibility of algorithm deliverability was assessed by the percentage of patients with successful completion (primary objective). RESULTS: Twenty-five patients were eligible (N = 25): at baseline, 22 took PERT (100% on suboptimal doses, 54.5% taking incorrectly) and 3 initiated PERT because of PEI symptoms. Algorithm completion (20 of 25, 80%) confirming deliverability by dietitians (11 of 12, 92%) and clinical nurse specialists (9 of 13, 69%). Symptom resolution occurred in 8 of 19 (42%), 3 of 7 (43%), and 1 of 3 (33%) patients at first, second, and third reviews, respectively; advice compliance was between 63% and 86%. CONCLUSIONS: This algorithm provides a structured method to titrate PERT. At diagnosis, all patients with PBC should be assessed for PEI and adequate PERT initiated. Regular reviews are required for timely symptom resolution and adequate escalation, facilitating differential diagnosis if refractory symptoms exist.

Structurally diverse biflavonoids from the fruits of Citrus medica L. var. sarcodactylis Swingle and their hypolipidemic and immunosuppressive activities.

The fruit of Citrus medica L. var. sarcodactylis Swingle is not only used as a traditional medicinal plant, but also served as a delicious food. Six new (3'→7″)-biflavonoids (1-6), and twelve known biflavonoid derivatives (7-18) were isolated and characterized from the fruits of C. medica L. var. sarcodactylis Swingle for the first time. Their structures were determined by extensive and comprehensive analyzing NMR, HR-ESI-MS, UV, and IR spectral data coupled with the data described in the literature. Compounds (1-18) were evaluated for their hypolipidemic activities with Orlistat as the positive control, and assayed for their immunosuppressive activities with Dexamethasone as the positive control, respectively. Among them, compounds (1-3) exhibited moderate inhibition of pancreatic lipase activity by inhibiting 68.56 ± 1.40%, 56.18 ± 1.57%, 53.51 ± 1.59% of pancreatic lipase activities at the concentration of 100 µM, respectively. Compounds (4-6) and 8 showed potent immunosuppressive activities with the IC50 values from 16.83 ± 1.32 to 50.90 ± 1.79 µM. The plausible biogenetic pathway and preliminary structure activity relationship of the selected compounds were scientifically summarized and discussed in this study.

Curative role of mesenchymal stromal cells in chronic pancreatitis: Modulation of MAPK and TGF-ß1/SMAD factors.

BACKGROUND AND OBJECTIVE: Living organisms respond to physical, chemical, and biological threats with a potent inflammatory response which alters organ cell signaling and leads to dysfunction. We evaluated the therapeutic effect of bone marrow-based mesenchymal stromal cell (BM-MSC) transplanted in rats to preserve tissue integrity and to restore homeostasis and function in the pancreatitis experimental pattern. METHODS: This study involved 40 adult male Wister rats. Repeated L-arginine injections caused chronic pancreatitis (CP), leading to the development of pancreatic damage and shifting the intracellular signaling pathways. Rats were then infused with BM-MSC labeled with PKH26 fluorescent linker dye for 12 weeks. RESULTS: Cell-surface indicators of BM-MSCs such as CD 90 and CD29 were expressed with the lack of CD34 expression. BM-MSC treatment considerably improved the alterations induced in a series of inflammatory markers, including IL-18, TNF-α, CRP, PGE2, and MCP-1. Furthermore, improvement was found in digestive enzymes and lipid profile with amelioration in myeloperoxidase activity. BM-MSC treatment also regulated the (TGF-/p-38MPAK/SMAD2/3) signaling factors that enhances repair of damaged pancreatic tissue, confirmed by reversed alteration of histopathological examination. CONCLUSION: our results further bring to light the promise of cell transplant therapy for chronic pancreatitis.

Determination of Activation Energies and the Optimum Temperatures of Hydrolysis of Starch by α-Amylase from Porcine Pancreas.

The present paper reports the determination of the activation energies and the optimum temperatures of starch hydrolysis by porcine pancreas α-amylase. The parameters were estimated based on the literature data on the activity curves versus temperature for starch hydrolysis by α-amylase from porcine pancreas. It was assumed that both the hydrolysis reaction process and the deactivation process of α-amylase were first-order reactions by the enzyme concentration. A mathematical model describing the effect of temperature on porcine pancreas α-amylase activity was used. The determine deactivation energies Ea were from 19.82 ± 7.22 kJ/mol to 128.80 ± 9.27 kJ/mol, the obtained optimum temperatures Topt were in the range from 311.06 ± 1.10 K to 326.52 ± 1.75 K. In turn, the values of deactivation energies Ed has been noted in the range from 123.57 ± 14.17 kJ/mol to 209.37 ± 5.17 kJ/mol. The present study is related to the starch hydrolysis by α-amylase. In the industry, the obtained results the values Ea, Ed, Topt can be used to design and optimize starch hydrolysis by α-amylase porcine pancreas. The obtained results might also find application in research on the pharmaceutical preparations used to treat pancreatic insufficiency or prognosis of pancreatic cancer.

Sulfiredoxin-1 attenuates injury and inflammation in acute pancreatitis through the ROS/ER stress/Cathepsin B axis.

Acinar cell injury and the inflammatory response are critical bioprocesses of acute pancreatitis (AP). We investigated the role and underlying mechanism of sulfiredoxin-1 (Srxn1) in AP. Mild AP was induced by intraperitoneal injection of cerulein and severe AP was induced by partial duct ligation with cerulein stimulation or intraperitoneal injection of L-arginine in mice. Acinar cells, neutrophils, and macrophages were isolated. The pancreas was analyzed by histology, immunochemistry staining, and TUNEL assays, and the expression of certain proteins and RNAs, cytokine levels, trypsin activity, and reactive oxygen species (ROS) levels were determined. Srxn1 was inhibited by J14 or silenced by siRNA, and overexpression was introduced by a lentiviral vector. Transcriptomic analysis was used to explore the mechanism of Srxn1-mediated effects. We also evaluated the effect of adeno-associated virus (AAV)-mediated overexpression of Srxn1 by intraductal administration and the protection of AP. We found that Srxn1 expression was upregulated in mild AP but decreased in severe AP. Inhibition of Srxn1 increased ROS, histological score, the release of trypsin, and inflammatory responses in mice. Inhibition of Srxn1 expression promoted the production of ROS and induced apoptosis, while overexpression of Srxn1 led to the opposite results in acinar cells. Furthermore, inhibition of Srxn1 expression promoted the inflammatory response by accumulating and activating M1 phenotype macrophages and neutrophils in AP. Mechanistically, ROS-induced ER stress and activation of Cathepsin B, which converts trypsinogen to trypsin, were responsible for the Srxn1 inhibition-mediated effects on AP. Importantly, we demonstrated that AAV-mediated overexpression of Srxn1 attenuated AP in mice. Taken together, these results showed that Srxn1 is a protective target for AP by attenuating acinar injury and inflammation through the ROS/ER stress/Cathepsin B axis.

Inhibition of α-glucosidase, pancreatic lipase, and antioxidant property of Myrcia hatschbachii D. Legrand containing gallic and ellagic acids / Inhibición de la α-glucosidasa, la lipasa pancreática y la propiedad antioxidante de Myrcia hatschbachii D. Legrand que contiene ácidos gálico y elágico

Several species of the Myrcia genus have been used in folk medicine to treat diabetes. Therefore, the aim of this work was to investigate the inhibitory activity of α-glucosidase and pancreatic lipase in the crude extract (EBF) and in the ethyl acetate fraction (FFA) of Myrcia hatschbachii, as well as to identify isolated phenolic compounds and to evaluate the antioxidant property and preliminary in vitro toxicity against Artemia salina. EBF (IC50: 3.21 µg/mL) and FFA (IC50: 1.14 µg/mL) showed inhibitory activity superior to acarbose (IC50: 193.65 µg/mL). In addition, they showed inhibitory effects of pancreatic lipase (IC50: 556.58 µg/mL for EBF and 532.68 µg/mL for FFA), antioxidant potential, absence of preliminary toxicity and presence of gallic andellagic acids in FFA. The relevant results in the inhibition of α-glucosidase and pancreatic lipase motivate new studies for the development of herbal medicines that assist in the treatment of diabetic patients.

Varias especies del género Myrcia se han utilizado en la medicina popular para tratar la diabetes. Por lo tanto, el objetivo de este trabajo fue investigar la actividad inhibitoria de la α-glucosidasa y la lipasa pancreática en el extracto crudo (EBF) y en la fracción de acetato de etilo (FFA) de Myrcia hatschbachii, así como identificar compuestos fenólicos aislados y evaluar la propiedad antioxidante y toxicidad in vitro preliminar contra Artemia salina. EBF (IC50: 3.21 µg/mL) y FFA (IC50: 1.14 µg/mL) mostraron una actividad inhibitoria superior a la acarbosa (IC50: 193.65 µg/mL). Además, mostraron efectos inhibitorios de la lipasa pancreática (IC50: 556.58 µg/mL para EBF y 532.68 µg/mL para FFA), potencial antioxidante, ausencia de toxicidad preliminar y presencia de ácidos gálico y elágico en FFA. Los resultados relevantes en la inhibición de la α-glucosidasa y la lipasa pancreática motivan nuevos estudios para el desarrollo de medicamentos a base de hierbas que ayudan en el tratamiento de pacientes diabéticos.

Drug therapies for reducing gastric acidity in people with cystic fibrosis.

BACKGROUND: Malabsorption of fat and protein contributes to poor nutritional status in people with cystic fibrosis. Impaired pancreatic function may also result in increased gastric acidity, leading in turn to heartburn, peptic ulcers and the impairment of oral pancreatic enzyme replacement therapy. The administration of gastric acid-reducing agents has been used as an adjunct to pancreatic enzyme therapy to improve absorption of fat and gastro-intestinal symptoms in people with cystic fibrosis. It is important to establish the evidence regarding potential benefits of drugs that reduce gastric acidity in people with cystic fibrosis. This is an update of a previously published review. OBJECTIVES: To assess the effect of drug therapies for reducing gastric acidity for: nutritional status; symptoms associated with increased gastric acidity; fat absorption; lung function; quality of life and survival; and to determine if any adverse effects are associated with their use. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic and non-electronic database searches, handsearches of relevant journals,  abstract books and conference proceedings. Both authors double checked the reference lists of the searches Most recent search of the Group's Trials Register: 26 April 2021. On the 26 April 2021 further searches were conducted on the clinicaltrials.gov register to identify any ongoing trials that may be of relevance. The WHO ICTRP database was last searched in 2020 and is not currently available for searching due to the Covid-19 pandemic. SELECTION CRITERIA: All randomised and quasi-randomised trials involving agents that reduce gastric acidity compared to placebo or a comparator treatment. DATA COLLECTION AND ANALYSIS: Both authors independently selected trials, assessed trial quality and extracted data. MAIN RESULTS: The searches identified 40 trials; 17 of these, with 273 participants, were suitable for inclusion, but the number of trials assessing each of the different agents was small. Seven trials were limited to children and four trials enrolled only adults. Meta-analysis was not performed, 14 trials were of a cross-over design and we did not have the appropriate information to conduct comprehensive meta-analyses. All the trials were run in single centres and duration ranged from five days to six months. The included trials were generally not reported adequately enough to allow judgements on risk of bias. However, one trial found that drug therapies that reduce gastric acidity improved gastro-intestinal symptoms such as abdominal pain; seven trials reported significant improvement in measures of fat malabsorption; and two trials reported no significant improvement in nutritional status. Only one trial reported measures of respiratory function and one trial reported an adverse effect with prostaglandin E2 analogue misoprostol. No trials have been identified assessing the effectiveness of these agents in improving quality of life, the complications of increased gastric acidity, or survival. AUTHORS' CONCLUSIONS: Trials have shown limited evidence that agents that reduce gastric acidity are associated with improvement in gastro-intestinal symptoms and fat absorption. Currently, there is insufficient evidence to indicate whether there is an improvement in nutritional status, lung function, quality of life, or survival. Furthermore, due to the unclear risks of bias in the included trials, we are unable to make firm conclusions based on the evidence reported therein. We therefore recommend that large, multicentre, randomised controlled clinical trials are undertaken to evaluate these interventions.

Pactacin is a novel digestive enzyme in teleosts.

Generally, animals extract nutrients from food by degradation using digestive enzymes. Trypsin and chymotrypsin, one of the major digestive enzymes in vertebrates, are pancreatic proenzymes secreted into the intestines. In this investigation, we report the identification of a digestive teleost enzyme, a pancreatic astacin that we termed pactacin. Pactacin, which belongs to the astacin metalloprotease family, emerged during the evolution of teleosts through gene duplication of astacin family enzymes containing six cysteine residues (C6astacin, or C6AST). In this study, we first cloned C6AST genes from pot-bellied seahorse (Hippocampus abdominalis) and analyzed their phylogenetic relationships using over 100 C6AST genes. Nearly all these genes belong to one of three clades: pactacin, nephrosin, and patristacin. Genes of the pactacin clade were further divided into three subclades. To compare the localization and functions of the three pactacin subclades, we studied pactacin enzymes in pot-bellied seahorse and medaka (Oryzias latipes). In situ hybridization revealed that genes of all three subclades were commonly expressed in the pancreas. Western blot analysis indicated storage of pactacin pro-enzyme form in the pancreas, and conversion to the active forms in the intestine. Finally, we partially purified the pactacin from digestive fluid, and found that pactacin is novel digestive enzyme that is specific in teleosts.

Severe Genotype, Pancreatic Insufficiency and Low Dose of Pancreatic Enzymes Associate with Abnormal Serum Sterol Profile in Cystic Fibrosis.

BACKGROUND: Several factors could lead to lipid disturbances observed in cystic fibrosis (CF). This study aimed to assess sterol homeostasis in CF and define potential exogenous and endogenous determinants of lipid dysregulation. METHODS: The study involved 55 CF patients and 45 healthy subjects (HS). Sterol concentrations (µg/dL) were measured by gas chromatography/mass spectrometry. CF was characterised by lung function, pancreatic status, liver disease and diabetes coexistence, Pseudomonas aeruginosa colonisation and BMI. CFTR genotypes were classified as severe or other. RESULTS: Campesterol and ß-sitosterol concentrations were lower (p = 0.0028 and p < 0.0001, respectively) and lathosterol levels (reflecting endogenous cholesterol biosynthesis) were higher (p = 0.0016) in CF patients than in HS. Campesterol and ß-sitosterol concentrations were lower in patients with a severe CFTR genotype, pancreatic insufficiency and lower pancreatic enzyme dose (lipase units/gram of fat). In multiple regression analyses, ß-sitosterol and campesterol concentrations were predicted by genotype and pancreatic insufficiency, whereas cholesterol and its fractions were predicted by phytosterol concentrations, age, dose of pancreatic enzymes, nutritional status and genotype. CONCLUSIONS: Independent determinants of lipid status suggest that malabsorption and pancreatic enzyme supplementation play a significant role in sterol abnormalities. The measurement of campesterol and ß-sitosterol concentrations in CF patients may serve for the assessment of the effectiveness of pancreatic enzyme replacement therapy and/or compliance, but further research is required.

One-step modification to identify dual-inhibitors targeting both pancreatic triglyceride lipase and Niemann-Pick C1-like 1.

Pancreatic triglyceride lipase (PTL) and Niemann-Pick C1-like 1 (NPC1L1) have been identified as attractive therapeutic targets for obesity and hypercholesteremia, respectively. Obesity and hypercholesteremia usually co-exist, however no dual-inhibitors against PTL and NPC1L1 were reported for the treatment of obesity patients with hypercholesteremia so far. In this work, molecular hybridization-based one-step modification screening identified a potent dual-inhibitor against PTL and NPC1L1. Compound P1-11 has IC50 values of 2.1 µM against PTL through covalent binding, as well as significantly reduces cholesterol absorption in a non-competitive inhibitory manner. Molecule docking and molecular dynamics studies revealed the reason of its activity to both PTL and NPC1L1. Moreover, the gene and protein expression levels of PTL and NPC1L1 were also determined respectively after the treatment of P1-11. Development of dual-inhibitors against PTL and NPC1L1 could provide novel treatment options for obesity patients with hypercholesteremia. The results of current research would great support the development of dual-inhibitors against PTL and NPC1L1.

Natural Isoflavones and Semisynthetic Derivatives as Pancreatic Lipase Inhibitors.

Obesity, now widespread all over the world, is frequently associated with some chronic diseases. Thus, there is a growing interest in the prevention and treatment of obesity. To date, the only antiobesity drug is orlistat, a natural product-derived pancreatic lipase (PL) inhibitor with some undesired side effects. In the last decades, many natural compounds or derivatives have been evaluated as potential PL inhibitors, and natural polyphenols are among the most promising for possible exploitation as antiobesity agents. However, few studies have been devoted to isoflavones. In this work, we report a study on the PL inhibitory properties of a small library of semisynthetic isoflavone derivatives together with the natural leads daidzein (1), genistein (2), and formononetin (3). In vitro lipase inhibition assay showed that 2 is the most promising PL inhibitor. Among synthetic isoflavones, the hydroxylated and brominated derivatives were more potent than their natural leads. Detailed studies through fluorescence measurements and kinetics of lipase inhibition showed that 2 and the bromoderivatives 10 and 11 have the greatest affinity for PL. Docking studies corroborated these findings highlighting the interactions between isoflavones and the enzyme, confirming that hydroxylation and bromination are useful modifications.

Paeonone A, a novel nonanortriterpenoid from the roots of Paeonia lactiflora.

Paeonone A (1), a unique nonanortriterpenoid, and a new octanortriterpenoid, paeonone B (2), were isolated from the roots of Paeonia lactiflora, together with a known analogue, palbinone (3). Paeonone A (1) is the first example of naturally occurring nonanortriterpenoid with a diketo acid group. Extensive NMR and HRESIMS experiments were applied to identify the structures of 1 and 2, and their absolute configurations were solved by single-crystal X-ray diffraction and ECD data. Biological properties of 1-3 were explored against pancreatic lipase and cancer cell lines.

Positional preferences in flavonoids for inhibition of ribonuclease A: Where "OH" where?

Flavonoids are a class of polyphenols that possess diverse properties. The structure-activity relationship of certain flavonoids and resveratrol with ribonuclease A (RNase A) has been investigated. The selected flavonoids have a similar skeleton and the positional preferences of the phenolic moieties toward inhibition of the catalytic activity of RNase A have been studied. The results obtained for RNase A inhibition by flavonoids suggest that the planarity of the molecules is necessary for effective inhibitory potency. Agarose gel electrophoresis and precipitation assay experiments along with kinetic studies reveal Ki values for the various flavonoids in the micromolar range. Minor secondary structural changes of RNase A were observed after interaction with the flavonoids. An insight into the specific amino acid involvement in the binding of the substrate using docking studies is also presented. The dipole moment of the flavonoids that depends on the orientation of the hydroxyl groups in the molecule bears direct correlation with the inhibitory potency against RNase A. The direct association of this molecular property with enzyme inhibition can be exploited for the design and development of inhibitors of proteins.

Initial experience of irreversible electroporation for locally advanced pancreatic cancer in a Korean population.

BACKGROUND: Locally advanced pancreatic cancer (LAPC) is one of the most aggressive malignancies. Irreversible electroporation (IRE) is a novel technique that uses a non-thermal ablation to avoid vessel or duct injury. PURPOSE: To investigate the safety and efficacy of IRE for the management of LAPC in a Korean population. MATERIAL AND METHODS: Twelve patients (median age 64 years; age range 46-73 years) treated between December 2015 and March 2017 underwent intraoperative IRE for LAPC. Technical success and clinical outcomes, including complications, serum pancreatic enzyme levels, overall survival (OS), and progression-free survival (PFS), were evaluated. RESULTS: Tumors were located in the pancreas head in 7 (58.3%) patients and in the body/tail in 5 (41.7%) patients. The median tumor diameter in the longest axis was 3.1 cm. Vascular invasion was observed in all patients and bowel abutment in 3 (25%) patients. Technical success was achieved in all patients. The median serum levels of amylase and lipase were 55 U/L and 31 U/L, respectively, at baseline, increased to 141.5 U/L (P = 0.008) and 53 U/L (P = 0.505), respectively, one day after IRE, and normalized after one week. The rate of 30-day mortality of unknown relation was 8.3% (one individual experienced massive hematemesis 12 days after IRE). The median OS from diagnosis and IRE was 24.5 months and 13.5 months, respectively. The median PFS from diagnosis and IRE was 19.2 months and 8.6 months, respectively. CONCLUSION: For patients with LAPC, IRE appears to be a promising treatment modality with an acceptable safety profile.

Postoperative hyperamylasemia (POH) and acute pancreatitis after pancreatoduodenectomy (POAP): State of the art and systematic review.

BACKGROUND: Postoperative hyperamylasemia is a frequent finding after pancreatoduodenectomy, but its incidence and clinical implications have not yet been analyzed systematically. The aim of this review is to reappraise the concept of postoperative hyperamylasemia with postoperative acute pancreatitis, including its definition, interpretation, and correlation. METHODS: Online databases were used to search all available relevant literature published through June 2019. The following search terms were used: "pancreaticoduodenectomy," "amylase," and "pancreatitis." Surgical series reporting data on postoperative hyperamylasemia or postoperative acute pancreatitis were selected and screened. RESULTS: Among 379 screened studies, 39 papers were included and comprised data from a total of 9,220 patients. Postoperative hyperamylasemia was rarely defined in most of these series, and serum amylase values were measured at different cutoff levels and reported on different postoperative days. The actual levels of serum amylase activity and the representative cutoff levels required to reach a diagnosis of postoperative acute pancreatitis were markedly greater on the first postoperative days and tended to decrease over time. Most studies analyzing postoperative hyperamylasemia focused on its correlation with postoperative pancreatic fistula and other postoperative morbidities. The incidence of postoperative acute pancreatitis varied markedly between studies, with its definition completely lacking in 40% of the analyzed papers. A soft pancreatic parenchyma, a small pancreatic duct, and pathology differing from cancer or chronic pancreatitis were all predisposing factors to the development of postoperative hyperamylasemia. CONCLUSION: Postoperative hyperamylasemia has been proposed as the biochemical expression of pancreatic parenchymal injury related to localized ischemia and inflammation of the pancreatic stump. Such phenomena, analogous to those associated with acute pancreatitis, could perhaps be renamed as postoperative acute pancreatitis from a clinical standpoint. Patients with postoperative acute pancreatitis experienced an increased rate of all postoperative complications, particularly postoperative pancreatic fistula. Taken together, the discrepancies among previous studies of postoperative hyperamylasemia and postoperative acute pancreatitis outlined in the present review may provide a basis for stronger evidence necessary for the development of universally accepted definitions for postoperative hyperamylasemia and postoperative acute pancreatitis.

Association between faecal pH and fat absorption in children with cystic fibrosis on a controlled diet and enzyme supplements dose.

BACKGROUND: Despite treatment with pancreatic enzyme replacement therapy (PERT), patients with cystic fibrosis (CF) can still suffer from fat malabsorption. A cause could be low intestinal pH disabling PERT. The aim of this study was to assess the association between faecal pH (as intestinal pH surrogate) and coefficient of fat absorption (CFA). Additionally, faecal free fatty acids (FFAs) were quantified to determine the amount of digested, but unabsorbed fat. METHODS: In a 24-h pilot study, CF patients followed a standardised diet with fixed PERT doses, corresponding to theoretical optimal doses determined by an in vitro digestion model. Study variables were faecal pH, fat and FFA excretion, CFA and transit time. Linear mixed regression models were applied to explore associations. RESULTS: In 43 patients, median (1st, 3rd quartile) faecal pH and CFA were 6.1% (5.8, 6.4) and 90% (84, 94), and they were positively associated (p < 0.001). An inverse relationship was found between faecal pH and total fat excretion (p < 0.01), as well as total FFA (p = 0.048). Higher faecal pH was associated with longer intestinal transit time (p = 0.049) and the use of proton pump inhibitors (p = 0.009). CONCLUSIONS: Although the clinical significance of faecal pH is not fully defined, its usefulness as a surrogate biomarker for intestinal pH should be further explored. IMPACT: Faecal pH is a physiological parameter that may be related to intestinal pH and may provide important physiopathological information on CF-related pancreatic insufficiency. Faecal pH is correlated with fat absorption, and this may explain why pancreatic enzyme replacement therapy is not effective in all patients with malabsorption related to CF. Use of proton pump inhibitors is associated to higher values of faecal pH. Faecal pH could be used as a surrogate biomarker to routinely monitor the efficacy of pancreatic enzyme replacement therapy in clinical practice. Strategies to increase intestinal pH in children with cystic fibrosis should be targeted.

Acute pancreatitis in intraductal papillary mucinous neoplasms correlates with pancreatic volume and epithelial subtypes.

BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is associated with acute pancreatitis (AP) in some cases, however its causes have not been fully elucidated. We investigated the association of the incidence of AP with epithelial subtypes and pancreatic volume in IPMN. METHODS: This retrospective study included 182 consecutive surgically resected IPMN patients between January 2000 and December 2018. The relationship between the incidence of AP and epithelial subtypes of IPMN and pancreatic volume was investigated. Epithelial subtypes of IPMN were classified into gastric (G type: N = 116), intestinal (I type: N = 49), pancreatobiliary (PB type: N = 14), and oncocytic types (O type: N = 3). Pancreatic volume of the contrast-enhanced computed tomography scan was measured using Ziostation2 software. Histological pancreatic parenchymal atrophy was also evaluated. RESULTS: AP occurred more frequently in I-types (I-type vs. G-type, 22.4% [11/49] vs 3.4% [4/116], P = 0.003) and PB-types (PB type vs. G-type, 35.7% [5/14] vs. 3.4% [4/116], P = 0.007) in comparison with G-types, which constituted the majority of the resected IPMNs. AP occurred more frequently in I-type patients with high pancreatic volumes (I-type with high pancreatic volume vs. I-type with low pancreatic volume, 37.0% [10/27] vs. 4.7% [1/21], P = 0.02). However, histological atrophy did not show an additional influence on the association between the incidence of AP and epithelial subtypes. The elevation of serum pancreatic enzymes was not significantly related to epithelial subtypes. CONCLUSION: Epithelial subtypes and the degree of pancreatic volume may be closely associated with the incidence of AP in IPMN.